This invention relates to a pharmaceutical formulation containing a physiologically active peptides or protein as an active principle.
A number of physiologically active peptides and proteins are currently used for therapeutic purposes. Enzymatic degradation and poor absorption of these substances from the intestinal tract have historically limited their administration to the parenteral route. The blood level of a drug is a function of the rate of its uptake by the living body (bioavailability) and the rate of its removal from the body (clearance). In the case of the oral administration of peptides or proteins, poor absorption from the intestinal tract is the main factor that precludes the dose-dependent delivery of the drug into the blood stream by this route.
Attempts have been made to increase the intestinal absorption of proteinous drugs by the use of formulations that protect the drugs from enzymatic degradation and/or enhance the uptake into the intestinal mucosa. These include a combination of insulin and a chymotrypsin-inhibitor (J. Pharm. Pharmcol., 37 (1985), 545-549); coating with azoaromatic copolymers (Science, 233 (1986), 1081-1084); a combination of vasopressin and aprotinin as a proteolytic enzyme inhibitor (J. Pharm. Sci., 77 (1988), 33-38); a solid solution of insulin in a mixture of stearic acid and a surfactant sold under the trademark "Brij" (J. Pharm. Pharmcol., 33 (1981), 733-734); and the like. However, none of these approaches have been proven satisfactory. They are not suited for application to proteinous drugs in general. Some of these techniques require the use of co-ingredients which have not been established to be pharmaceutically acceptable. Others often exhibit undesirable side effects such as vomiting.
By the present invention, there is provided an enteric formulation of physiologically active proteins or peptides (hereinafter referred to as "proteinous drug") in which the active principle is easily absorbed from the intestinal Tract and delivered into the blood stream in a substantially dose-dependent manner. The present invention utilizes such co-ingredients that have been proven to be pharmaceutically acceptable or inert and, therefore, are those commonly used for the manufacture of various forms of solid medicaments for oral administration. Accordingly, the formulation of the invention is substantially free from any side effect or otherwise adverse action due to the presence of such co-ingredients. One of the significant advantages of this invention resides in the fact that its application is not limited to a particular class of proteinous drugs but finds use in proteinous products in general.
Many proteinous drugs occur as a solution which must be stored in a cool place, or a lyophilized product which requires subsequent reconstitution in saline or sterile water immediately before use. By the present invention, such drugs may be formulated in a solid medicament for oral administration which is stable for a reasonable period of time and may be administered directly to the patient without the need for reconstitution or other processing. This also achieves transportation and storage advantages over current preparations.
Other objects and advantages of the present invention will become apparent to those skilled in the art as the description proceeds.